Cancer is a group of diseases in which abnormal cells divide without control. Cancer cells can invade nearby tissues and can spread through the bloodstream and lymphatic system to other parts of the body. There are several main types of cancer. Carcinoma is cancer that begins in the skin or in tissues that line or cover internal organs. Sarcoma is cancer that begins in bone, cartilage, fat, muscle, blood vessels, or other connective or supportive tissue. Leukemia is cancer that starts in blood-forming tissue such as the bone marrow, and causes large numbers of abnormal blood cells to be produced and enter the bloodstream. Lymphoma and multiple myeloma are cancers that begin in the cells of the immune system.
Several treatments are available for cancer, including surgery and radiation for localised disease, and drugs that destroy cancer cells (chemotherapy). Chemotherapy plays a significant part in cancer treatment, as it is required for the treatment of advanced cancers with distant metastasis and often helpful for tumor reduction before surgery (neoadjuvant therapy). It is also used following surgery or radiation (adjuvant therapy) to destroy any remaining cancer cells or prevent recurrence of the cancer.
Many anti-cancer drugs have been developed based on various modes of action: alkylating agents that act directly on the DNA (such as cisplatin, carboplatin, oxaliplatin, busulfan, chlorambucil, cyclophosphamide, ifosfamide, dacarbazine); antimetabolites that interfere with DNA and RNA synthesis (such as 5-fluorouracil, capecitabine, 6-mercaptopurine, methotrexate, gemcitabine, cytarabine (ara-C), fludarabine); anthracyclines that interfere with enzymes involved in DNA replication (such as daunorubicin, doxorubicin, epirubicin, idarubicin, mitoxantrone); microtubule disrupters (taxanes such as paclitaxel and docetaxel or Vinca alkaloids such as vinblastine, vincristine, and vinorelbine); topoisomerase inhibitors (such as etoposide, doxorubicin, topotecan and irinotecan); hormone therapy (such as tamoxifen, flutamide) and recently introduced targeted therapy (such as the inhibitors of EGFR cetuximab, gefitinib or the protein tyrosine kinase inhibitor imatinib) are the most frequently used.
Cancer chemotherapy may consist of a single drug or combinations of drugs that are delivered in cycles. A cycle consists of treatment with one or more drugs followed by a period of rest.
The development of chemotherapy in the last decades has significantly improved the treatment of cancer, resulting in effective treatments in some types of cancers, and improved survival or time to progression in others. Currently, most chemotherapy is administered intravenously; however, oral chemotherapy drugs are gaining wider use.
Unfortunately, most chemotherapy drugs cannot difference between a cancer cell and a healthy cell. Therefore, chemotherapy often affects the body's normal tissues and organs which results in complication of treatments, or side effects. In addition to the problems they cause, side effects can prevent doctors from delivering the prescribed dose of chemotherapy, reducing the probability of a correct treatment of cancer. Most frequent side effects of chemotherapy are anemia, neutropenia, thrombocytopenia, fatigue, alopecia, nausea and vomiting, mucositis and pain.
Palmar plantar Erythrodysesthesia (PPE) was first described by Zuehlke in 1974 as a erythematous eruption of the palms and soles associated with mitotane therapy (Zuehlke, R. K. Dermatologica, 1974, 148(2), 90-92). PPE is a distinctive and relatively frequent toxic reaction related to some chemotherapeutic agents. It is a painful swelling and erythematous rash, located in the palms and soles, often preceded by dysesthesia, usually in the form of a tingling sensation, and often associated with edema. The rash may become bollous and then desquamate without scarring, and pain gradually increases. Erythema may also occur in periungal areas. Generally it is confined to the hands and feet, the hands are usually more severely affected than the feet.
Histologically PPE shows mild spongiosis, scattered necrotic and dyskeratotic keratynocites and vacuolar degeneration of the basal layer. Dermal changes in most cases include dilated blood vessels, papillary edema, and a sparse superficial perivascular limphohistiocytic infiltrate that can be found in varying degrees in the epidermis.
PPE is clearly distinct from other adverse skin reactions and is reviewed in Nagore E. et al, Am J Clin Dermatol. 2000, 1(4), 225-234 which is incorporated herein by reference in its entirety.
The severity of PPE can be classified according to the following WHO grades:                1. Dysesthesia/paresthesia, tingling in the hands and feet.        2. Discomfort in holding objects and upon walking, painless swelling or erythema.        3. painful erythema and swelling of palms and soles, periungual erythema and swelling.        4. Desquamation, ulceration, blistering, severe pain.        
Another grading is based on the US National Cancer Institute criteria:
1. Skin changes or dermatitis without pain (E.g erythema, peeling)
2. Skin changes with pain, not interfering with function
3. Skin changes with pain interfering with function
Among the agents that have been reported to cause PPE, Fluorouracil (5-FU), Capecitabine (Xeloda®), pegylated Liposomal doxorubicin (Caelyx®/Doxil®), Cytarabine (Cytosar-U®), Floxuridine (FUDR®), Tegafur and Idarubicin (Idamycin®) are the most frequent inducers.
Fluorouracil is a fluorinated pyrimidine that is metabolized intracellularly to its active form, fluorouridine monophosphate, that inhibits DNA synthesis. It is indicated for several types of cancer, among others as adjuvant or palliative therapy in breast, colorectal, gastric and pancreatic cancer. The benefits of fluorouracil based adjuvant chemotherapy in reducing the risk of relapse and prolonging survival in patients with resected colon cancer are well established, particularly in stage III disease, Survival advantages were demonstrated with bolus intravenous fluorouracil (425 mg/m2) plus leucovorin (a biomodulator) according to the Mayo Clinic regimen (five days, monthly, for six months), or the Roswell par regimen (weekly bolus, six of every eight weeks, for eight months) (Sun W. et al Curr Oncol Rep. 2005 May; 7(3):181-5). For metastatic colon cancer a 24 hour continuous infusion of high dose 5-FU (2600 mg/m2) and leucovorin weekly for 6 weeks followed by a 1 or 2 week rest period (AIO protocol) showed improved progression free survival compared with the Mayo protocol (Köhne et al J Clin Oncol, 2003, vol 21, no. 20, 3721-3728).
New combinations of fluorouracil are emerging, such as with oxaliplatin (FOLFOX) or irinotecan (FOLFIRI) showing survival benefits in the treatment of colorectal cancer (Goldberg, Oncologist 2005; 10 Suppl 3:40-8. Review). Most of these combinations use infusional fluorouracil.
In spite of the obvious benefits of Fluorouracil as a chemotherapy, the incidence of PPE is frequent with the bolus and high dose continuous infusion regimens. This is a reason for dose reduction or interruption of the treatment. In metastatic colon cancer, the prolonged 5-FU24H/LV schedule resulted in higher incidence of PPE (34%) compared with the Mayo protocol (13%) (J Clin Oncol, 1998, vol 16, 3537-3541). Infusional fluorouracil is also responsible for PPE in the treatment of breast cancer, see for example Smith I E et al. Ann. Oncol. 2004, 15(5) 751-758.
Capecitabine (Xeloda®) is a prodrug, an oral fluoropyrimidine carbonate that is activated into fluorouracil in tumor tissue by thymidine phosphorylase. It is used as adjuvant therapy for the treatment of colon cancer, as first line therapy for metastatic colorectal cancer, and for the treatment of advanced or metastatic breast cancer. In a recently reported phase III study, capecitabine was compared with fluorouracil+leucovorin (Mayo protocol) as adjuvant treatment for stage III colon cancer (Twelves C. et al., N Engl J Med 2005, 352, 2696-2704). Concerning efficacy, capecitabine was shown to be equivalent to fluorouracil+leucovorin. As first line treatment for metastatic colorectal cancer, capecitabine achieved response rates superior to those achieved with the Mayo Clinic regimen with equivalent progression free survival and overall survival (Van Cutsem E. et al. Br J Cancer 2004, 90:1190-1197). Concerning toxicity, in both cases capecitabine showed less incidence of severe grade 3 or 4 stomatitis and neutropenia. However, the incidence of hand-foot syndrome (PPE) was significantly higher with capecitabine than with fluorouracil+leucovorin, being as high as 49-60% for all grades and 17% for severe grades. This resulted in dose reduction, delay or interruption of the treatment. In metastatic breast cancer the same situation arises, capecitabine alone or in combination with docetaxel showed improved efficacy versus docetaxel, but one of the most common dose limiting adverse effects is PPE.
In view of the above, although capecitabine has the important advantage of being an oral drug and more convenient for the patient, in particular in combination treatments, palmar planar erythrodysesthesia remains one of the main causes for concern when using this drug.
Another drug that is frequently associated with PPE is pegylated liposomal doxorubicin, i.e. doxorubicin hydrochloride encapsulated in long-circulating stealth liposomes with surface bound methoxypolyethylene glycol. The pegylation protects the liposomes from detection by the immune system allowing them to reach a tissue or organ characterized by a higher permeability of the endothelium, such as a tumor. Liposomal doxorubicin is used for the treatment of advanced ovarian cancer and of metastatic breast cancer. PPE with this drug is related to the schedule, and the incidence is relatively high: 37.4% for all grades, with 16.4% for severe grades were reported in ovarian cancer. Toxicity can be reduced by a reduction in dose intensity (for example from 50 mg/m2 every 4 weeks to 40 mg/m2, Rose P G, The Oncologist, 2005, 10:205-214).
Palmar plantar erythrodysesthesia is thus an important side effect for the mentioned chemotherapeutic agents. However, little is known of its causes and at present there is no therapy or prophylaxis for PPE proved to be effective. Chemotherapy reduction, delay or withdrawal can be effective in reducing or eliminating PPE, but at the cost of seriously compromising the chemotherapeutic treatment of cancer.
Some of the few treatments that have been proposed are: cold compresses or ice packs, especially during chemotherapy; elevating hands or feet; skin hydration; emollient skin creams containing lanolin, lactic acid, petroleum jelly (for example Bag Balm® a petroleum lanolin based ointment with hydroxyquinoline sulfate as antiseptic ingredient, or Aquaphor®), and topical or oral corticosteroids such as dexamethasone.
Pyridoxine (vitamin B6) has been used to decrease the pain from PPE (Fabian et al. Invest. New Drugs 1990, 8:57-63; Lauman M K et al. ASCO Proceedings, 2001, abstract 1565) and it appears to provide some symptomatic benefit in patients being treated with capecitabine.Amifostine, a cytoprotective agent, has been used to try to prevent PPE in patients being treated with liposomal doxorubicin (Lyass O. et al, ASCO Proceedings, 2001, abstract 2148).U.S. Pat. No. 6,060,083 discloses the use of topical DMSO for the treatment of PPE, in particular when caused by pegylated liposomal doxorubicin.U.S. Pat. No. 6,979,688 describes the topical use of uracil ointment for the treatment of PPE induced by fluorouracil or a precursor thereof.
None of the proposed treatments has yet been able to effectively treat or prevent PPE. It is clear that an effective treatment of PPE is still needed, in order to untie the full potential of chemotherapeutic agents such as fluorouracil, capecitabine or pegylated liposomal doxorubicin and the different regimens and combinations in which they are used.
Allopurinol is a structural isomer of hypoxanthine, that inhibits xanthine oxidase, an enzyme that converts oxypurines to uric acid. By blocking the production of uric acid, this agent decreases serum and urine concentrations of uric acid, thereby providing protection against uric acid-mediated end organ damage in conditions associated with excessive production of uric acid. It has been used for many years for the treatment or prevention of gout, hyperuricemia and kidney stones, through oral or parenteral systemic administration.
Allopurinol has also been reported for the treatment of mucositis, a frequent chemotherapy- or radiation-induced damage to the rapidly dividing cells lining the mouth, throat and gastrointestinal (GI) tract. Allupurinol is used in the form of mouthwashes (dispersion in water) (porta C. et al, Am J clin Oncol. 1994, Vol 17, no. 3, 246-247). An improved formulation for mouthwashes comprising allopurinol, carboxymethylcellulose and water is described in JP-3106817. Hanawa et al. in Drug Dev Ind Pharm 2004, 30(2) 151-161 describe another mouthwash comprising allopurinol, polyethyleneoxide and carrageenan.
Dagher et al., canadian journal of Hospital pharmacy, vol. 40, no. 5 1987, page 189 discloses the use of allopurinol mouthwash and vaginal 0.1% cream for the treatment of 5-FU-Induced mucositis.
Allopurinol has also been administered systemically to modulate the 5-fluorouracil myelosuppresion, in particular granulocytopenia (Woolley at al. J. of Clinical Oncology, 1985 vol. 3, no. 1, 103-109). However, preclinical studies showed antagonism between the two drugs.
EP278040 describes the use of pteridines or xanthine oxidase inhibitors, among other allopurinol, for the treatment of genetically caused, degenerative retina diseases such as retinopathia pigmentosa, in the form of topically administrable eye drops or eye creams. There is no specific disclosure in this document of a topical composition containing allopurinol.
WO94/05293 and WO94/05291 describe synergistic compositions comprising methylsuphonylmethane (MSM) and at least one of oxypurinol or allopurinol and their use for the treatment of skin conditions, diseases and injuries such as burns, dermatitis, hyperkeratosis, sun exposure, skin ageing, etc. Oxypurinol or allopurinol are described as enhancing the skin healing or repairing properties of MSM.
None of the cited documents mentions or suggests that allopurinol would be useful for the treatment or prevention of palmar planar erythrodysesthesia.